| First Author | Yang H | Year | 2017 |
| Journal | J Intern Med | Volume | 282 |
| Issue | 1 | Pages | 76-93 |
| PubMed ID | 28464519 | Mgi Jnum | J:256590 |
| Mgi Id | MGI:6116080 | Doi | 10.1111/joim.12619 |
| Citation | Yang H, et al. (2017) The haptoglobin beta subunit sequesters HMGB1 toxicity in sterile and infectious inflammation. J Intern Med 282(1):76-93 |
| abstractText | BACKGROUND: Extra-corpuscular haemoglobin is an endogenous factor enhancing inflammatory tissue damage, a process counteracted by the haemoglobin-binding plasma protein haptoglobin composed of alpha and beta subunits connected by disulfide bridges. Recent studies established that haptoglobin also binds and sequesters another pro-inflammatory mediator, HMGB1, via triggering CD163 receptor-mediated anti-inflammatory responses involving heme oxygenase-1 expression and IL-10 release. The molecular mechanism underlying haptoglobin-HMGB1 interaction remains poorly elucidated. METHODS: Haptoglobin beta subunits were tested for HMGB1-binding properties, as well as efficacy in animal models of sterile liver injury (induced by intraperitoneal acetaminophen administration) or infectious peritonitis (induced by cecal ligation and puncture, CLP, surgery) using wild-type (C57BL/6) or haptoglobin gene-deficient mice. RESULTS: Structural-functional analysis demonstrated that the haptoglobin beta subunit recapitulates the HMGB1-binding properties of full-length haptoglobin. Similar to HMGB1-haptoglobin complexes, the HMGB1-haptoglobin beta complexes also elicited anti-inflammatory effects via CD163-mediated IL-10 release and heme oxygenase-1 expression. Treatment with haptoglobin beta protein conferred significant protection in mouse models of polymicrobial sepsis as well as acetaminophen-induced liver injury, two HMGB1-dependent inflammatory conditions. CONCLUSIONS: Haptoglobin beta protein offers a novel therapeutic approach to fight against various inflammatory diseases caused by excessive HMGB1 release. |
